Testosterone derivative

ABSTRACT

The invention is the novel androgen (7α,17β)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4en-3one (MENT undecanoate). This compound distinguishes favourably from other testosterone derivatives in that it has a good solubility in oily media. It particularly exhibits a good dissolved potency relative to testosterone. The compound is particularly suitable for administration by means of injection.

[0001] The invention is in the field of androgenic hormones, morespecifically derivatives of testosterone.

[0002] Testosterone derivatives are known. Testosterone itself, thenatural male hormone, has many known drawbacks as far as methods ofadministration are concerned. It has a short-lasting activity, isinsoluble in the usual pharmaceutically acceptable media, and is notvery potent. The more potent dihydrotestosterone (5α-reduced form oftestosterone) is considered a health-risk, notably for the prostate. Asomewhat better soluble derivative is testosterone undecanoate, which isknown as the active substance in the product Andriol®.

[0003] More potent androgens are 7α-methyl-19-nortestosterone (MENT) andrelated compounds, such as disclosed in FR 4.521 M and U.S. Pat. No.5,342,834. However, MENT suffers from a bad solubility and shortduration of action.

[0004] New androgenic hormones are needed which inter alia satisfy thedemands connected with new areas of interest, such as male contraceptionand male HRT (hormone replacement therapy). Thus, e.g., malecontraception may comprise a regimen of administration of hormones inwhich a progestagen serves to achieve a contraceptive effect and anandrogen serves to supplement the resulting decreased testosteronelevel. Another option is that male contraception is performed with anandrogenic hormone alone. The regular androgen intake needed for thisrequires androgens which are improved as to potency and duration ofaction, and for which a practical way of administration is available. Aslow a frequency of administration being desired, there is a demand forandrogens which have such physico-chemical properties as to be renderedinto a solution, particularly a solution by which the androgen can beadministered via injection, preferably once a week or less frequent, ororally via a capsule to be taken, e.g., daily. This means that a basicdesired property for a novel androgen is that it has an improvedsolubility in one or more pharmaceutically acceptable liquids.

[0005] Even more desired is an androgen which has a favourablerelationship of potency and solubility, as a weak androgen will requiremore of it to be dissolved in order to attain the same activity as amore potent androgen. This means an androgen having an improved relative“dissolved potency”, hereinafter referred to as RDP, wherein the RDP ofa given androgen in a given medium is the product of its androgenicpotency relative to that of the natural male hormone testosterone andits solubility in the medium relative to that of testosterone.

[0006] It is an object of the invention to provide an androgenic hormonewhich satisfies the above demand. To this end, the invention is thecompound (7α,17β)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-one, whichhas the following structural formula:

[0007] The compound of the invention is also to be referred to as7α-methyl-19-nortestosterone undecanoate, in short MENT undecanoate.

[0008] The compound of the invention has a significantly bettersolubility than could be expected on the basis of the known testosteronederivatives. Moreover, the compound of the invention has a surprisinglyhigher RDP than the known compounds.

[0009] The compound of the invention can be prepared by esterificationof the 17-OH group of MENT with undecanoic acid or derivatives thereof.This esterification may be carried out using methods well known in theart or readily available from the chemical literature, for example,using methods and catalysts described in Advanced Organic Chemistry, J.March, 4th Ed, pages 1281-1282, 1992. MENT can be prepared as disclosedin FR 4.521 M and U.S. Pat. No. 5,342,834.

[0010] The invention also pertains to the compound MENT undecanoate as amedicine. The compound of the invention being a potent androgen, it canbe used in, inter alia, male contraception and male or female hormonereplacement therapy. Thus the invention also pertains to a method oftreatment of androgen insufficiency, by administering to a human male orfemale an effective amount of MENT undecanoate. The invention also is inthe use of MENT undecanoate for the preparation of a medicine fortreating androgen insufficiency. In the context of the invention, theterm “androgen insufficiency” is to be understood to pertain to allkinds of diseases, disorders, and symptoms in which a male or a femalesuffers from too low a testosterone level, such as in hypogonadal men.In particular, the androgen insufficiency to be treated by the compoundof the invention is the reduction of the testosterone level which ahuman male incurs as a result of age (the compound of the invention isthen used for male hormone replacement therapy), or when he is subjectto male contraception. In the context of male contraception, thecompound of the invention especially serves to neutralise the effect ofregimens of male hormone contraception in which a sterilitant such as aprogestagen or LHRH (luteinizing hormone releasing hormone) isadministered regularly, e.g. daily, or it is used as the sole malecontraceptive substance.

[0011] The invention also relates to pharmaceutical formulationscomprising MENT undecanoate and a pharmaceutically acceptable carrier.Thus the carrier may be in a solid form or liquid form, and theformulation may be an oral dosage unit such as a tablet or, preferably,an oral solution, e.g. in a capsule. Methods and compositions for makingsuch dosage units are well-known to those skilled in the art. Forexample, conventional techniques for making tablets and pills,containing active ingredients, are described in the standard reference,Gennaro et al, Remington's Pharmaceutical Sciences, (18th ed., MackPublishing Company, 1990, see especially Part 8: PharmaceuticalPreparations and Their Manufacture). The compound can also beadministered via an implant, a patch, or any other suitable device forthe sustained release of an androgen composition. The preferred oraldosage unit is that of a capsule containing the compound of theinvention taken up in a liquid medium as described below.

[0012] In order to benefit most from the compound's androgenic activity,administration of the compound dissolved in an oil is preferred, i.e.either orally as above, and notably via (intramuscular) injection. MENTundecanoate has a solubility in oily media, which makes it particularlysuitable for a liquid pharmaceutical formulation comprising MENTundecanoate dissolved in a pharmaceutically acceptable oil. Suitableoils are, e.g., arachis oil, oleic acid, ricinus oil, sesam oil and thelike. Arachis oil is preferred.

[0013] For injection the preferred injection device is a needlelessinjection system, e.g. as described in U.S. Pat. No. 5,599,302. To thisend the compound may also be suspended in an aqueous medium, but theabove solutions in oil are preferred. Methods and compositions formaking liquids suitable for parenteral administration are known in theart, see e.g. Remington's, pages 1545 ff.

[0014] For oral administration, any capsule made from a pharmaceuticallyacceptable wall material can be employed. Methods and compositions formaking capsules suitable for oral administration are known in the art,see e.g. Remington's, pages 1658 ff. A preferred material is a softgelsuch as used for Andriol® capsules.

[0015] The invention also pertains to a method of treatment of androgeninsufficiency, by administering to a human male, by injection or bymeans of an oral dosage unit, an effective amount of MENT undecanoatedissolved in a pharmaceutically acceptable oil. The invention also is inthe use of MENT undecanoate for the preparation of a medicine fortreating androgen insufficiency by injecting into a human male aneffective amount of MENT undecanoate dissolved in a pharmaceuticallyacceptable oil, or by orally administering such an oily solution.

[0016] The dose of and regimen of administration MENT undecanoate, or apharmaceutical composition thereof, to be administered will obviouslydepend on the therapeutic effect to be achieved and will vary with theroute of administration, and the age and condition of the individualsubject to whom the medicament is to be administered, and/or or theparticular contraceptive or HRT regimen in which it is used. Typicaldoses are 100 mg or more per three months upon intramuscularadministration and 50-250 mg, more preferably 80 mg per day upon oraladministration.

[0017] The invention will be further explained hereinafter withreference to the following Examples.

EXAMPLE 1

[0018] (7α,17β)-7-Methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-one.

[0019] A total of 2.23 grams of commercially available undecanoylchloride were added to a stirred solution of 1.58 grams of(7α,17β)-17-hydroxy-7-methylestr-4-en-3-one at 0-5° C. The reactionmixture was allowed to reach room temperature and stirred overnight.Thereafter, ice was added and after stirring for another 2 hours thereaction mixture was poured into ice-water, containing 4 ml of conc.H₂SO₄, followed by ethyl acetate extraction. The organic layers werewashed with water, cold 1 N NaOH solution and brine, dried on sodiumsulfate, filtered and evaporated in vacuo. The residue waschromatographed over silica. Elution with heptane-ethylacetate (4:1) andevaporation gave a greasy solid that was collected. Yield 1.42 g,[α]_(D) ²⁰=+36° (c=1; dioxane), MS (ESI): 456.

[0020] (17β)-17-[(1-Oxoundecyl)oxy]androst-4-en-3-one

[0021] “Testosterone undecanoate” is commercially available.

EXAMPLE 2

[0022] About 20-30 mgs of compound were powdered and then dissolved inas little solvent as necessary to dissolve all the visible particles.Dissolution was accomplished by heating in a waterbath of 50° C. andshaking on a Vortex™ shaker for 15 minutes. The solubility wascalculated by determining the amount of compound (in mg) dissolved perml of solvent.

COMPARATIVE EXAMPLE

[0023] The solubility and the androgenic potency of the compound of theinvention and three reference compounds was used to determine RDP. Theresults are given in the tables below. With regard to clinicallydesirable anabolic and antigonadotropic effects (androgenic effects),MENT is ten times more potent than testosterone in rats (Kumar N et al,Endocrinology 130: 3677-3683 (1992) and J Steroid Biochem Molec Biol 52:105-112 (1995)) and monkeys (Cummings D et al, J Clin Endocrinol Metab83, 4212-4219 (1998)). The RDP is determined as follows:$\frac{{Solubility}\quad {of}\quad {compound}}{{{Solubility}\quad {of}\quad {testosterone}}\quad} \times {potency}\quad {of}\quad {compound}\quad {relative}\quad {to}\quad {that}\quad {of}\quad {testosterone}$

TABLE 1 solubility solubility compound arachis oil oleic acidtestosterone <<0.1 mg/ml ˜25 mg/ml MENT ≦0.1 mg/ml ˜15 mg/mltestosterone undecanoate ˜45 mg/ml 200-250 mg/ml MENT undecanoate >200mg/ml ≧500 mg/ml

[0024] From the table it can be learned that the solubility of MENTundecanoate in arachis oil is much better than that of any of the otherandrogens. The solubility of MENT undecanoate in oleic acid is alsobetter than expected in view of that of the known androgens.

We claim:
 1. A kit for male contraception, comprising: a means for theadministration of a progestagen and a means for the administration of anandrogen, wherein the latter means is a pharmaceutical formulation,comprising: (7α,17β)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-one anda pharmaceutically acceptable carrier.
 2. The kit for male contraceptionaccording to claim 1, wherein the pharmaceutically acceptable carrier isa liquid in which(7α,17β)-7-methyl-17-[(1-oxoundecyl)oxy]estr-4-en-3-one is dissolved.